Understanding the Genetic Mechanisms of Cancer Drug Resistance Using Genomic Approaches

A major obstacle in precision cancer medicine is the inevitable resistance to targeted therapies. Tremendous effort and progress has been made over the past few years to understand the biochemical and genetic mechanisms underlying drug resistance, with the goal to eventually overcome such daunting challenges. Diverse mechanisms, such as secondary mutations, oncogene bypass, and epigenetic alterations, can all lead to drug resistance, and the number of known involved genes is growing rapidly, thus providing many possibilities to overcome resistance. The finding of these mechanisms and genes invariably requires the application of genomic and functional genomic approaches to tumors or cancer models. In this review, we briefly highlight the major drug-resistance mechanisms known today, and then focus primarily on the technological approaches leading to the advancement of this field.

TrendsThe emergence of drug resistance is a recurrent theme in targeted cancer therapies; thus, the understanding and conquering of drug resistance have become focal points in precision cancer medicine.While the biochemical and genetic mechanisms underlying drug resistance are diverse and complex, the state-of-art technologies (high-throughput sequencing, functional genomics, model systems, etc.) leading to the understanding of such mechanisms have been a consistent force driving the advancement of this field.Although many genes have been found to impact drug resistance, the limited convergence from multiple studies indicates that we are still at the beginning stage of unearthing the entire drug-resistance repertoire. New genomic technologies, preclinical models, and computational methodologies are poised to further accelerate the development of this new field.